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Vol. 17, Issue 6, 2604-2616, June 2006
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Departments of Pediatrics and Biochemistry and Molecular Biology, Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7
Submitted January 23, 2006;
Revised March 2, 2006;
Accepted March 22, 2006
Monitoring Editor: Sean Munro
Sphingomyelin (SM) and cholesterol are coregulated metabolically and associate physically in membrane microdomains involved in cargo sorting and signaling. One mechanism for regulation of this metabolic interface involves oxysterol binding protein (OSBP) via high-affinity binding to oxysterol regulators of cholesterol homeostasis and activation of SM synthesis at the Golgi apparatus. Here, we show that OSBP regulation of SM synthesis involves the endoplasmic reticulum (ER)-to-Golgi ceramide transport protein (CERT). RNA interference (RNAi) experiments in Chinese hamster ovary (CHO)-K1 cells revealed that OSBP and vesicle-associated membrane protein–associated protein (VAP) were required for stimulation of CERT-dependent ceramide transport and SM synthesis by 25-hydroxycholesterol and cholesterol depletion in response to cyclodextrin. Additional RNAi experiments in human embryonic kidney 293 cells supported OSBP involvement in oxysterol-activated SM synthesis and also revealed a role for OSBP in basal SM synthesis. Activation of ER-to-Golgi ceramide transport in CHO-K1 cells required interaction of OSBP with the ER and Golgi apparatus, OSBP-dependent Golgi translocation of CERT, and enhanced CERT–VAP interaction. Regulation of CERT by OSBP, sterols, and VAP reveals a novel mechanism for integrating sterol regulatory signals with ceramide transport and SM synthesis in the Golgi apparatus.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
Address correspondence to: Neale D. Ridgway ( nridgway{at}dal.ca)
Abbreviations used: C5-DMB-ceramide, N-[5-(5,7dimethyl boron dipyrromethenedifluoride)-1-pentanoyl]-D-sphingosine; CERT, ceramide transport protein; FFAT, two phenylalanines in an acidic tract; 25OH, 25-hydroxycholesterol; GlcCer, glucosylceramide; M
CD, methyl--cyclodextrin; NT, nontargeting; PtdEtn, phosphatidylethanolamine; PtdSer, phosphatidylserine; PtdIns-4-P, phosphatidylinositol-4-phosphate; OSBP, oxysterol binding protein; ORP, OSBP-related protein; RNAi, RNA interference; shRNA, short hairpin RNA; siRNA, short interfering RNA; SM, sphingomyelin; VAP, vesicle-associated membrane protein-associated protein.
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